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Elucidation of Mechanisms for the Growth of hepato-cellular carcinoma (HCC) with androgen receptor and development of new hormone therapy for HCC

Research Project

Project/Area Number 08457325
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionShimane Medical University

Principal Investigator

NAGASUE Naofumi  Shimane Medical University, Second Department of Surgery, Professor, 医学部, 教授 (40117198)

Co-Investigator(Kenkyū-buntansha) YAMANOI Akira  Shimane Med.Univ., Surg.Dept., Assistant, 医学部, 助手 (70281152)
KUBOTA Hirofumi  Shimane Med.Univ., Surg.Dept., Lecturer, 医学部, 講師 (00205147)
KOHNO Hitoshi  Shimane Med.Univ., Surg.Dept., Assoc.Prof., 医学部, 助教授 (60145951)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1996: ¥3,800,000 (Direct Cost: ¥3,800,000)
Keywordshepatocellular carcinoma / androgen / androgen receptor / tumor angiogenesis / growth factors / 5alpha-reductase / dihydrotestosterone / hormone therapy / サリドマイド / 腫瘍血管 / 肝化学発癌 / ヌードマウス / 細胞培養 / 抗アンドロゲン療法 / VEGF / PDECGF / ユ-ドマウス / TGF-β_1 / アポトーシス
Research Abstract

Using 50 surgical specimens of hepatocellular carcinoma (HCC), cell proli-ferative activity and apoptosis were evaluated in terms of transforming growth factor (TGF)-alpha and TGF-beta1 . It was elucidated that TGF-beta1 was associated with decreased proliferative activity in HGCs smaller than 5 cm but such mechanism was disrupted in larger tumors. The clinicopathologic significance of microvessel density (MVD) of HCC was evaluated in terms of vascular endothelial growth factor (VEOF) and platelet-derived endothelial cell growth factor (PD-ECGF). Although both angiogenic factors were not associated with tumor MVD, VEOF was related with angiogenesis of cirrhotic liver and PD-ECGF was associated with angiogenesis of hepatitis C virus induced chronic liver disease. Density of relatively large tumor vessels stained with Factor 8 antibody was an independent risk factor for intra-hepatic tumor recurrence following curative hepatic. resection.
The growth of androgen receptor (AR) positive HCC … More was suppressed when transplanted in normal female and castrated male nude mice, but the tumor growth in castrated male mice was completely recovered by the supplemen-tation of dihydrotestosterone (DHT). An AR inhibitor cyproterone acetate (CPA) suppressed or inhibited the growth of AR-positive HCC dose-dependently. CPA induced overexpression of TGF-beta1 in the tumor which possibly, caused cell cycle arrest at G1 phase and in addition apoptosis.
Following studies have not been accomplished as yet but are in progress at present. 5 alpha -reductase converts testosterone in target cells to dihydro-testosterone (DHT) which has a higher affinity to AR compared with testo-sterone and the highest hormonal activity among all androgens. Provided that DHT is most responsible for the growth of AR-positive HCC, the inhibition of 5alpha -reductase could be effective in prophylaxis and treatment of HCC.So far, we have found that a 5 alpha -reductase inhibitor FK143 is effective in suppressing the growth of AR-positive HCC in vivo and in vitro as well as the hepatocarcinogenic process in the Solt-Farber model in rats. Less

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Yu L et al: "Effects of castration and androgen replacement on tumour growth of human hepatocellular carcinoma in nude mice" Journal of Hepatology. 25. 362-369 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nagasue N et al: "Inhibition of growth and induction of TGF-β_1 in human hepatocellular carcinoma with androgen receptor -----" Journal of Hepatology. 25. 554-562 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yu L et al: "Heterogeneity in androgen receptor levels and growth response to dihydrotestosterone in sublines -------" Liver. 17. 35-40 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamaguchi M et al: "Growth kinetic study of human hepatocellular carcinoma using proliferating cell nuclear antigen and -------" Oncology. 54. 245-251 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] El-Assai ON et al: "Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular ---" Hepatology. 27. 1554-1562 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yamamoto A et al: "Thymidine phosphorylase(platelet-derived endothelial cell growth factor), microvessel density and clinical -------" Journal of Hepatology. 29. 290-299 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Liqun Yu, Naofumi Nagasue, Minekazu Yamaguchi, Yu-Chung Chang: "Effects of castration and androgen replacement on tumour growth of human hepatocellular carcinoma in nude mice." Journal of Hepatology. 25. 362-369 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Naofumi Nagasue, Liqun Yu, Minekazu yamaguchi, Hitoshi Kohno, Mitsuo Tachibana, Hirofumi Kubota: "Inhibition of growth and induction of TGF-beta_1 in human hepatocellular carcinoma with androgen receptor by cyproterone acetate in male nude mice." Journal of Hepatology. 25. 554-562 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Liqun Yu, Hirofumi Kubota, Katsuyuki Imai, Minekazu Yamaguchi, Naofumi Nagasue: "Heterogeneity in androgen receptor levels and growth response to dihydrotestosterone in sublines derived from human hepato-cellular carcinoma line (KYN-1)." Liver. 17. 35-40 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Minekazu Yamaguchi, Liqun Yu, Yoshitaka Hishikawa, Akira Yamanoi, Hirofumi Kubota, Naofumi Nagasue: "Growth kinetic study of human hepatocellular carcinoma using proliferating cell nuclear antigen and Lewis Y antigen : Their correlation with transforming growth factor-alpha and beta_1." Oncology. 54. 245-251 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Osama N El-Assal, Akira Yamanoi, Yukiko Soda, Minekazu Yamaguchi, Akitaka Yamamoto, Naofumi Nagasue: "Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver : Possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver." Hepatology. 27. 1554-1562 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Akitaka Yamamoto, Dipok Kumar Dhar, Osama Nazmy El-Assal, Masahiko Igarashi, Hideki Tabara, Naofumi Nagasue: "Thymidine phosphorylase (platelet-derived endothelial cell growth factor), microvessel density and clinical outcome in hepatocellular carcinoma." Journal of Hepatology. 29. 290-299 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Assal ON et al.: "Clinical significance of microvessel density and VEGF expression in hepatocellular carcinoma and surrounding liver Possible involvement of VEGF in the angiogenesis" Hepatology. 27(6). 1554-1562 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamamoto A et al.: "Correlation between thymidine phosphorylase (PDECGF) and microvessel density in hepatocellular carcimona" Journal of hepatology. 29. 290-299 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yamaguchi M et al.: "Growth kinetic study of human hepatocellular carcinoma using proliferating cell nuclear antigen・・・・・" Oncology. 54(3). 245-251 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] El-Assal ON et al.: "Proposal of invasiveness score to predict recurrence and survival after curative resection for・・・・・" Surgery. 122(3). 571-577 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] El-Assal ON et al.: "Clinical significance of microvessel density and VEGF expression in hepatocellular carcinoma and・・・・・" Hepatology. (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamamoto A et al.: "Correlation between thymidine phosphorylase(PDECGF)and microvessel density in hepatocellular carcinoma" Journal of Hepatology. (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Yu L,Nagasue N,Yamaguchi M,Chang Y-C: "Effects of castration and androgen replacement on tumour growth of human hepatocellular carcinoma in nude mice" Journal of Hepatology. 25(3). 362-369 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Nagaseu N,Yu L,Yamaguchi M,Kohno H,Tachibana M,Kubota H: "Inhibition of growth and induction of TGF-β_1 in human hepatocellular carcinoma with androgen receptor by cyproterone acetate in male nudemice" Journal of Hepatology. 25(4). 554-562 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yu L,Kubota H,Imai K,Yamaguchi M,Nagasue N: "Heterogeneity in androgen receptor levels and growth response to dihydrotestosterone in sublines derived from human hepatocellular carcinoma line(KYN-1)" Liver. 17(1). 35-40 (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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